Methods for acute and long-term treatment of drug addiction

ABSTRACT

This invention is directed to a method of treating opioid or opioid-like drug addiction, including acute and post-acute withdrawal symptoms, comprising treating an addicted patient with noribogaine at a dosage that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL (AUC/24 h) under conditions where the QT interval prolongation does not exceed about 50 milliseconds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of International Application No.PCT/US14/19692, filed Feb. 28, 2014, and claims priority under 35 U.S.C.section 119(e) of U.S. Provisional Application No. 61/945,746, filed onFeb. 27, 2014 and, U.S. Provisional Application No. 61/941,387, filed onFeb. 18, 2014, all of which are incorporated in their entirety herein byreference.

FIELD OF THE INVENTION

This invention is directed to a method of treating addiction to anopioid or opioid-like drug, including acute and post-acute withdrawalsymptoms, comprising treating an opioid-addicted patient withnoribogaine at a dosage that provides an average serum concentration ofabout 50 ng/mL to about 850 ng/mL (AUC/24 h), including under conditionswhere the QT interval prolongation does not exceed about 50milliseconds.

STATE OF THE ART

Substance addiction is a serious public health problem throughout theworld. Heroin and other opioids, including prescription painkillers, arewidely abused and account for a large percentage of illicit drug use.Opioid use is also linked to approximately 50% of violent crimes in theUnited States and costs the U.S. economy billions of dollars per year.

Acute withdrawal from drug dependence is characterized by dramatic andtraumatic symptoms, including sweating, racing heart, palpitations,muscle tension, tightness in the chest, difficulty breathing, tremor,nausea, vomiting, diarrhea, grand mal seizures, heart attacks, strokes,hallucinations and delirium tremens (DTs). Once acute withdrawalsymptoms have subsided, post-acute withdrawal syndrome can last formonths or years. Post-acute withdrawal symptoms include fatigue,depression, lack of motivation, and increased pain sensitivity.

Numerous treatments have been developed in attempts to ameliorate acuteand post-acute withdrawal symptoms. However, in most cases, treatment ofwithdrawal requires use of other addictive substances (e.g., morphine ormethadone). Treatment also requires that the addict attend a clinicdaily for an extended amount of time. Due to the severity and durationof withdrawal symptoms, opioid-addicted patients have a high rate ofrelapse. There is a significant need for effective, non-addictivetreatment for acute and post-acute opioid withdrawal symptoms.

While the prior art suggests that ibogaine at higher doses is useful asa treatment for addiction, use of ibogaine is associated withhallucinations and other negative side effects. In the United States,ibogaine is classified as a Schedule I controlled substance.

Noribogaine is a metabolite of ibogaine found in human, dog, rat andmonkey. Noribogaine compounds have been suggested to have a greater andlonger lasting activity in humans than ibogaine for reducing craving foraddictive substances and treating chemical dependency. U.S. Pat. No.6,348,456, incorporated by reference herein in its entirety, discloseshighly purified noribogaine and teaches that it should be provided atdosages from about 0.01 to about 100 mg per kg body weight per day totreat addiction, although no human data was provided showing aneffective dose to treat opioid or opioid-like drug addiction.

The therapeutic dosing of noribogaine for treating opioid or opioid-likedrug addiction in humans has not previously been addressed, especiallyas it relates to dosing protocols that are effective, as well as safe.Indeed, prior to the instant invention, it was uncertain as to whethernoribogaine could be administered at a dose which was therapeutic whileat the same time safe for patients.

SUMMARY

While noribogaine has been disclosed for treatment of substanceaddiction, its use in humans is complicated by the fact that the rangesin the prior art are exceptionally broad (0.01 to 1000 mg/kg bodyweight). Furthermore, human clinical studies demonstrate that the lowerdosing of noribogaine has minimal impact on withdrawal symptoms inaddicted patients. Thus, the previously disclosed broad range has nowbeen found to be insufficient for human therapy at the lower end of thisrange.

Moreover, the use of noribogaine imparts a dose dependent prolongationof the treated patient's QT interval, rendering higher dosing ofnoribogaine unacceptable. A prolonged QT interval is a marker ofpotential ventricular tachyarrhythmia which, and can result in death.For reasons that are not apparent, this prolongation increases in opioidaddicted patients as compared to healthy individuals.

The current invention is predicated on the surprising discovery thattreatment with a narrow dosage range of noribogaine or pharmaceuticallyacceptable salt or solvate thereof, between greater than about 1 mg/kgbody weight and about 8 mg/kg body weight, provides a therapeuticreduction in withdrawal symptoms and/or an increase in time toresumption of opioid use in opioid-addicted patients. Preferably, thedose range that provide both therapeutic results and an acceptable QTinterval prolongation of less than 50 milliseconds in opioid andopioid-like drug addicted humans is between about 1.3 mg per kg bodyweight and no more than about 4 mg per kg body weight and, morepreferably between about 1.3 mg per kg body weight and no more thanabout 3 mg per kg body weight, or any subrange or subvalue within theaforementioned ranges. Opioid-like drugs, including cocaine, ketamine,and methamphetamine, are not opioids but act through the opioidreceptors, and thus addiction to these drugs also can be treated withnoribogaine.

In a preferred embodiment, the narrow therapeutic doses of noribogaineor pharmaceutically acceptable salt or solvate described aboveunexpectedly do not prolong the QT interval to unacceptable levels inhuman addicted patients. It is expected that opioid or opioid-like drugaddicted patients will be administered therapeutic doses of noribogaineor pharmaceutically acceptable salt or solvate thereof in a clinicalsetting with cardiac monitoring. In some embodiments, the patient willbe pre-screened to evaluate tolerance for prolongation of QT interval,e.g., to determine whether the patient has any pre-existing cardiacconditions which would disqualify them from treatment with noribogaine.

Some aspects of the current invention are further predicated on thediscovery that even lower doses of noribogaine or pharmaceuticallyacceptable salt or solvate thereof, for example approximately 80% orless of the therapeutic dose, may be effective for prevention of relapseof opioid (or opioid-like drug) use in an opioid-addicted patienttreated to ameliorate their opioid use. That is, a lower dose ofnoribogaine can prevent a patient who is no longer physically addictedto opioid from relapsing to opioid use. Without being bound by theory,it is believed that a patient who is no longer physically addicted toopioids or opioid-like drug requires less noribogaine to prevent relapsebecause the opioid or opioid-like drug does not compete with noribogainefor receptor binding, and/or because desensitization of one or morereceptors in the brain by the opioid or opioid-like drug is reversedwhen the patient ceases to take the drug. This lower, maintenance doseof noribogaine results in a QT interval prolongation that does notrequire clinical cardiac monitoring.

In some embodiments, the therapeutic dose of noribogaine orpharmaceutically acceptable salt or solvate thereof administered to thepatient is sufficient to provide an average serum concentration of about50 ng/mL to about 850 ng/mL (area under the curve/24 hours, AUC/24 h),or any subrange or subvalue there between. In a preferred embodiment,the dose of noribogaine or pharmaceutically acceptable salt or solvatethereof administered to the patient provides an average serumconcentration of about 50 ng/mL to about 400 ng/mL (AUC/24 h).

In some embodiments, the patient is administered a high (therapeutic)dose of noribogaine or pharmaceutically acceptable salt or solvatethereof for a period of time to ameliorate the most significant withdrawsymptoms, and then is administered a lower (maintenance) dose to preventrelapse to opioid or opioid-like drug use. In some embodiments, thepatient is administered a therapeutic dose of noribogaine orpharmaceutically acceptable salt or solvate thereof for a period of timeto ameliorate the most significant withdraw symptoms, and then isadministered a decreasing (tapered) amount of noribogaine orpharmaceutically acceptable salt or solvate thereof over time until themaintenance dose is reached. In some embodiments, a high initialtherapeutic dose is administered, followed by administration of a lowertherapeutic dose. In some embodiments, the dose of noribogaine istapered over time from the high therapeutic dose to a lower therapeuticdose.

In some embodiments, the dose of noribogaine or pharmaceuticallyacceptable salt or solvate thereof that provides an average serumconcentration of about 50 ng/mL to about 850 ng/mL (AUC/24 h) isadministered as a single dose. In some embodiments, the dose ofnoribogaine or pharmaceutically acceptable salt or solvate thereof thatprovides an average serum concentration of about 50 ng/mL to about 850ng/mL (AUC/24 h) is administered as multiple doses. In some embodiments,the aggregate dose of noribogaine or pharmaceutically acceptable salt orsolvate thereof is from greater than about 1 mg/kg to about 8 mg/kg. Ina preferred embodiment, the aggregate dose of noribogaine orpharmaceutically acceptable salt or solvate thereof is from greater thanabout 1 mg/kg to about 4 mg/kg. In another preferred embodiment, theaggregate dose of noribogaine or pharmaceutically acceptable salt orsolvate thereof is from greater than about 1 mg/kg to 3 mg/kg.

In some embodiments, the serum concentration is sufficient to inhibit orameliorate said abuse while maintaining a QT interval of less than 500milliseconds (ms) during said treatment. In some embodiments, thetherapeutic dose of noribogaine or pharmaceutically acceptable salt orsolvate thereof provides prolongation of the QT interval of less than 80ms. In a preferred embodiment, the maintenance dose of noribogaine orpharmaceutically acceptable salt or solvate thereof providesprolongation of the QT interval of less than 50 ms. In some embodiments,the maintenance dose or therapeutic dose of noribogaine orpharmaceutically acceptable salt or solvate thereof providesprolongation of the QT interval of less than 30 ms. In a preferredembodiment, the maintenance dose of noribogaine or pharmaceuticallyacceptable salt or solvate thereof provides prolongation of the QTinterval of less than 20 ms. In one embodiment, the QT prolongation isequivalent to or less than that observed in patients receiving methadonetreatment. In a preferred embodiment, the patient is tested to determineQT interval before treatment with noribogaine, and if cliniciandetermines that the QT prolongation would be unacceptable risk,noribogaine therapy will be contraindicated.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 represents mean noribogaine concentration-time profiles inhealthy patients after single oral dosing with 3, 10, 30 or 60 mg doses.Inset: Individual concentration-time profiles from 0-12 h after a 10 mgdose.

FIG. 2 represents mean plasma noribogaine glucuronide concentration-timeprofiles in healthy patients after single oral 30 or 60 mg doses.

FIG. 3 illustrates the mean noribogaine concentration-time profile inopioid-addicted patients after a single oral 60 mg dose of noribogaine(gray diamonds). Mean noribogaine concentration-time profile inopioid-addicted patients after single oral 120 mg dose of noribogaine(black squares) was estimated based on values for patients receiving 60mg dose.

FIG. 4A illustrates hours to resumption of opioid substitution treatmentin patients given no treatment (light gray bar), or a single oral doseof noribogaine or placebo (60 mg, dark gray bar; 120 mg, black bar).Error bars represent standard deviation.

FIG. 4B illustrates the estimated serum noribogaine concentration inng/mL at time of resumption of opioid substitution treatment (OST) inpatients receiving single oral dose of noribogaine or placebo (60 mg,dark gray diamonds; 120 mg, black squares). Data is estimated based onthe concentration-time profile in FIG. 3.

FIG. 5A illustrates imputed results of noribogaine treated patientswherein the results represent hours to resumption of OST in patientsgiven no treatment (light gray bar), or a (imputed) single 120 mg doseof noribogaine (black bar). Error bars represent standard deviation.

FIG. 5B illustrates imputed results of noribogaine treated patientswherein the results represent the estimated serum noribogaineconcentration in ng/mL at time of resumption of OST in patientsreceiving a (imputed) single oral 120 mg dose of noribogaine (blacksquares). Data is estimated based on the concentration-time profile inFIG. 3.

DETAILED DESCRIPTION

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of this invention will be limited only by theappended claims.

The detailed description of the invention is divided into varioussections only for the reader's convenience and disclosure found in anysection may be combined with that in another section. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acompound” includes a plurality of compounds.

I. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein the followingterms have the following meanings.

The term “about” when used before a numerical designation, e.g.,temperature, time, amount, concentration, and such other, including arange, indicates approximations which may vary by (+) or (−) 10%, 5% or1%.

“Administration” refers to introducing an agent into a patient.Typically, an effective amount is administered, which amount can bedetermined by the treating physician or the like. Any route ofadministration, such as oral, topical, subcutaneous, peritoneal,intra-arterial, inhalation, vaginal, rectal, nasal, introduction intothe cerebrospinal fluid, or instillation into body compartments can beused. The agent may be administered by direct blood stream delivery,e.g. sublingual, intranasal, or intrapulmonary administration.

The related terms and phrases “administering” and “administration of”,when used in connection with a compound or pharmaceutical composition(and grammatical equivalents) refer both to direct administration, whichmay be administration to a patient by a medical professional or byself-administration by the patient, and/or to indirect administration,which may be the act of prescribing a drug. For example, a physician whoinstructs a patient to self-administer a drug and/or provides a patientwith a prescription for a drug is administering the drug to the patient.

“Periodic administration” or “periodically administering” refers tomultiple treatments that occur on a daily, weekly, or monthly basis.Periodic administration may also refer to administration of noribogaineor salt or solvate thereof one, two, three, or more times per day.Administration may be via transdermal patch, gum, lozenge, sublingualtablet, intranasal, intrapulmonary, oral administration, or otheradministration.

“Comprising” or “comprises” is intended to mean that the compositionsand methods include the recited elements, but not excluding others.“Consisting essentially of” when used to define compositions andmethods, shall mean excluding other elements of any essentialsignificance to the combination for the stated purpose. Thus, acomposition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) of the claimed invention.“Consisting of” shall mean excluding more than trace elements of otheringredients and substantial method steps. Embodiments defined by each ofthese transition terms are within the scope of this invention.

“Noribogaine” refers to the compound:

as well as noribogaine derivatives or pharmaceutically acceptable saltsand pharmaceutically acceptable solvates thereof. It should beunderstood that where “noribogaine” is mentioned herein, one morepolymorphs of noribogaine can be utilized and are contemplated. In someembodiments, noribogaine is noribogaine glucuronide. Noribogaine can beprepared by demethylation of naturally occurring ibogaine:

which is isolated from Tabernanth iboga, a shrub of West Africa.Demethylation may be accomplished by conventional techniques such as byreaction with boron tribromide/methylene chloride at room temperaturefollowed by conventional purification. See, for example, Huffman, etal., J. Org. Chem. 50:1460 (1985), which incorporated herein byreference in its entirety. Noribogaine can be synthesized as described,for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and2012/0253037, PCT Patent Publication No. WO 2013/040471 (includesdescription of making noribogaine polymorphs), and U.S. patentapplication Ser. No. 13/593,454, each of which is incorporated herein byreference in its entirety.

In some embodiments, the methods of the present disclosure entail theadministration of a prodrug of noribogaine that provides the desiredmaximum serum concentrations and efficacious average noribogaine serumlevels. A prodrug of noribogaine refers to a compound that metabolizes,in vivo, to noribogaine. In some embodiments, the prodrug is selected tobe readily cleavable either by a cleavable linking arm or by cleavage ofthe prodrug entity that binds to noribogaine such that noribogaine isgenerated in vivo. In one preferred embodiment, the prodrug moiety isselected to facilitate binding to the μ and/or κ receptors in the braineither by facilitating passage across the blood brain barrier or bytargeting brain receptors other than the μ and/or κ receptors. Examplesof prodrugs of noribogaine are provided in U.S. patent application Ser.No. 13/165,626, the entire content of which is incorporated herein byreference.

This invention is not limited to any particular chemical form ofnoribogaine, and the drug may be given to patients either as a freebase, solvate, or as a pharmaceutically acceptable acid addition salt.In the latter case, the hydrochloride salt is generally preferred, butother salts derived from organic or inorganic acids may also be used.Examples of such acids include, without limitation, those describedbelow as “pharmaceutically acceptable salts” and the like.

“Pharmaceutically acceptable composition” refers to a composition thatis suitable for administration to a human. Such compositions includevarious excipients, diluents, carriers, and such other inactive agentswell known to the skilled artisan.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts, including pharmaceutically acceptable partial salts, of acompound, which salts are derived from a variety of organic andinorganic counter ions well known in the art and include, by way ofexample only, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid,perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid,citric acid, malic acid, maleic acid, aconitic acid, salicylic acid,thalic acid, embonic acid, enanthic acid, oxalic acid and the like, andwhen the molecule contains an acidic functionality, include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like.

“Therapeutically effective amount” or “therapeutic amount” refers to anamount of a drug or an agent that, when administered to a patientsuffering from a condition, will have the intended therapeutic effect,e.g., alleviation, amelioration, palliation or elimination of one ormore manifestations of the condition in the patient. The therapeuticallyeffective amount will vary depending upon the patient and the conditionbeing treated, the weight and age of the subject, the severity of thecondition, the salt, solvate, or derivative of the active drug portionchosen, the particular composition or excipient chosen, the dosingregimen to be followed, timing of administration, the manner ofadministration and the like, all of which can be determined readily byone of ordinary skill in the art. The full therapeutic effect does notnecessarily occur by administration of one dose, and may occur onlyafter administration of a series of doses. Thus, a therapeuticallyeffective amount may be administered in one or more administrations. Forexample, and without limitation, a therapeutically effective amount ofnoribogaine, in the context of treating opioid or opioid-like drugdependency, refers to an amount of noribogaine that attenuates thedependency and/or symptoms of acute withdrawal for at least 2 hoursbeyond control (placebo), at least 5 hours beyond control, andpreferably at least 10 hours beyond control.

A “therapeutic level” of a drug is an amount of noribogaine orpharmaceutical salt or solvate thereof that is sufficient to treatopioid or opioid-like drug addiction or to treat, prevent, or attenuateacute withdrawal symptoms, but not high enough to pose any significantrisk to the patient. Therapeutic levels of drugs can be determined bytests that measure the actual concentration of the compound in the bloodof the patient. This concentration is referred to as the “serumconcentration.”

As defined herein, a “maintenance amount” of a drug is an amount,typically less than the therapeutically effective amount that providesattenuation and/or prevention of post-acute withdrawal syndrome in apatient. The maintenance amount of the compound is expected to be lessthan the therapeutically effective amount because the level ofinhibition does not need to be as high in a patient who is no longerphysically addicted to opioid or opioid-like drug. For example, amaintenance amount is preferably 80%, 70%, 60%, 50%, 40%, 30%, 20%, or10% less than a therapeutically effective amount, or any subvalue orsubrange there between.

“Treatment,” “treating,” and “treat” are defined as acting upon adisease, disorder, or condition with an agent to reduce or ameliorateharmful or any other undesired effects of the disease, disorder, orcondition and/or its symptoms. “Treatment,” as used herein, covers thetreatment of a human patient, and includes: (a) reducing the risk ofoccurrence of the condition in a patient determined to be predisposed tothe condition but not yet diagnosed as having the condition, (b)impeding the development of the condition, and/or (c) relieving thecondition, i.e., causing regression of the condition and/or relievingone or more symptoms of the condition. “Treating” or “treatment of” acondition or patient refers to taking steps to obtain beneficial ordesired results, including clinical results such as the reduction ofsymptoms. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to: treating opioid or opioid-likedrug addiction; treating, preventing, and/or attenuating acutewithdrawal symptoms; treating, preventing, and/or attenuating long-term(post-acute) withdrawal symptoms; and preventing relapse of opioid oropioid-like drug use.

As used herein, the term “patient” refers to humans.

As used herein, the term “opiate” refers to naturally-occurringalkaloids found in the opium poppy. These include codeine, morphine,oripavine, pseudomorphine, and thebaine. Also included are opium, opiumpoppy, poppy straw, and extracts and concentrates thereof.

As used herein, the term “opioid” refers to naturally-occurring opiatesand synthetic or semi-synthetic opioids that have psychoactive effects.Non-limiting examples include acetyl-alpha-methylphentanyl,acetylmethadol, alfentanil, allylprodine, alphacetylmethadol,alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl,alphaprodine, anileridine, benzylmorphine, benzethidine,betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl,betameprodine, betacetylmethadol, beta-hydroxyfentanyl,beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine,bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene,codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine,diampromide, diamorphone, diethylthiambutene, dihydrocodeine,dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol,dimethyl-thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl,furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levoalphacetylmethadol, levomethorphan,levorphanol, levophenacylmorphan, levomoramide, lofentanil, loperamide,laudanum, meperidine, meptazinol, metazocine, methadone,3-methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine,MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), myrophine, narceine,nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, para-fluorofentanyl, paregoric, PEPAP(1-(-2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine,phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, racemoramide, racemethorphan, racemorphan, remifentanil,sufentanil, tapentadol, thiofentanyl, tilidine, tramadol, trimeperidine,mixtures of any of the foregoing, salts of any of the foregoing,derivatives of any of the foregoing, and the like. The term opioids alsoencompasses opioid intermediates, including4-cyano-2-dimethylamino-4,4-diphenyl butane,2-methyl-3-morpholino-1,1-diphenylpropane-carboxylic acid,4-cyano-1-methyl-4-phenylpiperidine,ethyl-4-phenylpiperidine-4-carboxylate, and1-methyl-4-phenylpiperidine-4-carboxylic acid. Many opioids are ScheduleI or Schedule II drugs in the US.

As used herein, the term “opioid-like drug” refers to any illicit drugthat binds to one or more opioid receptor and causes opioid-likeaddiction. Acute and long-term withdrawal symptoms from cessation of useof such drugs may be similar to those from cessation of opioids.Opioid-like drugs include amphetamine, methamphetamine, ketamine, andcocaine.

As used herein, the term “QT interval” refers to the measure of the timebetween the start of the Q wave and the end of the T wave in theelectrical cycle of the heart. Prolongation of the QT interval refers toan increase in the QT interval.

As used herein, the terms “addiction” and “dependence” are usedinterchangeably to refer to the patient's inability to stop using theopioid or opioid-like drug, even when it would be in his/her bestinterest to stop. The DSMIV-TR criteria for dependency include:

-   -   Dependence or significant impairment or distress, as manifested        by 3 or more of the following during a 12 month period:    -   1. Tolerance or markedly increased amounts of the substance to        achieve intoxication or desired effect or markedly diminished        effect with continued use of the same amount of substance    -   2. Withdrawal symptoms or the use of certain substances to avoid        withdrawal symptoms    -   3. Use of a substance in larger amounts or over a longer period        than was intended    -   4. Persistent desire or unsuccessful efforts to cut down or        control substance use    -   5. Involvement in chronic behavior to obtain the substance, use        the substance, or recover from its effects    -   6. Reduction or abandonment of social, occupational or        recreational activities because of substance use    -   7. Use of substances even though there is a persistent or        recurrent physical or psychological problem that is likely to        have been caused or exacerbated by the substance.

The term “solvate” as used herein refers to complexes with solvents inwhich noribogaine is reacted or from which noribogaine is precipitatedor crystallized. For example, a complex with water is known as a“hydrate”. Solvates of noribogaine are within the scope of theinvention. It will be appreciated by those skilled in organic chemistrythat many organic compounds can exist in more than one crystalline form.For example, crystalline form may vary based on the solvate used. Thus,all crystalline forms of noribogaine or the pharmaceutically acceptablesolvates thereof are within the scope of the present invention.

II. METHODS OF THE INVENTION

As will be apparent to the skilled artisan upon reading this disclosure,the present invention provides a method for treating opioid oropioid-like drug, abuse including acute and post-acute withdrawalsymptoms, in a patient addicted to opioid or opioid-like drug,comprising administering to the patient a dosage of noribogaine orpharmaceutically acceptable salt or solvate thereof.

Therapeutic Administration

In one aspect, this invention relates to treatment of acute withdrawalfrom an opioid or opioid-like drug in an addicted patient comprisingadministration of a therapeutically effective amount of noribogaine orpharmaceutically acceptable salt or solvate thereof.

In one aspect, this invention relates to a method for treating opioid oropioid-like drug abuse in an addicted patient, comprising administeringto the patient a dosage of noribogaine or pharmaceutically acceptablesalt or solvate thereof that provides an average serum concentration ofabout 50 ng/mL to about 850 ng/mL (AUC/24 h), said concentration beingsufficient to inhibit or ameliorate said abuse while maintaining a QTinterval of less than about 500 ms during said treatment.

In one aspect, this invention relates to a method for attenuatingwithdrawal symptoms in a human patient susceptible to such symptoms dueto opioid or opioid-like drug addiction, comprising administering to thepatient a dosage of noribogaine or pharmaceutically acceptable salt orsolvate thereof that provides an average serum concentration of about 60ng/mL to about 400 ng/mL (AUC/24 h), said concentration being sufficientto attenuate said symptoms while maintaining a QT interval of less thanabout 500 ms during said treatment. In some embodiments, theconcentration is sufficient to attenuate said symptoms while maintaininga QT interval of less than about 470 ms during treatment. Preferably,the concentration is sufficient to attenuate said symptoms whilemaintaining a QT interval of less than about 450 ms during treatment. Inone embodiment, the concentration is sufficient to attenuate saidsymptoms while maintaining a QT interval of less than about 420 msduring treatment. In one embodiment, the withdrawal symptoms aresymptoms of acute withdrawal.

In one aspect, this invention relates to a method for attenuatingwithdrawal symptoms in a human patient susceptible to such symptoms dueto opioid or opioid-like drug addiction, comprising administering to thepatient a dosage of noribogaine or pharmaceutically acceptable salt orsolvate thereof that provides an average serum concentration of about 50ng/mL to about 400 ng/mL (AUC/24 h), said concentration being sufficientto attenuate said symptoms while maintaining a QT interval of less thanabout 500 ms during said treatment. In some embodiments, theconcentration is sufficient to attenuate said symptoms while maintaininga QT interval of less than about 470 ms during treatment. Preferably,the concentration is sufficient to attenuate said symptoms whilemaintaining a QT interval of less than about 450 ms during treatment. Inone embodiment, the concentration is sufficient to attenuate saidsymptoms while maintaining a QT interval of less than about 420 msduring treatment. In one embodiment, the withdrawal symptoms aresymptoms of acute withdrawal.

In one embodiment, the average serum concentration of noribogaine isfrom about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800ng/mL. In one embodiment, the average serum concentration of noribogaineis from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700ng/mL. In one embodiment, the average serum concentration of noribogaineis from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about600 ng/mL. In a preferred embodiment, the average serum concentration ofnoribogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mLto about 500 ng/mL. In one embodiment, the average serum concentrationof noribogaine is from about 50 ng/mL to about 400 ng/mL, or about 60ng/mL to about 400 ng/mL. In one embodiment, the average serumconcentration of noribogaine is from about 50 ng/mL to about 300 ng/mL,or about 60 ng/mL to about 300 ng/mL. In one embodiment, the averageserum concentration of noribogaine is from about 50 ng/mL to about 200ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, theaverage serum concentration of noribogaine is from about 50 ng/mL toabout 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The rangesinclude both extremes as well as any subranges between.

In one embodiment, the dosage or aggregate dosage of noribogaine or saltor solvate thereof is from greater than about 1 mg/kg to about 8 mg/kgbody weight per day. The aggregate dosage is the combined dosage, forexample the total amount of noribogaine or pharmaceutically acceptablesalt or solvate thereof administered over a 24-hour period where smalleramounts are administered more than once per day. In one embodiment, thedosage or aggregate dosage of noribogaine or salt or solvate thereof isfrom about 1.3 mg/kg to about 7 mg/kg body weight. In one embodiment,the dosage or aggregate dosage of noribogaine or salt or solvate thereofis from about 1.3 mg/kg to about 6 mg/kg body weight. In one embodiment,the dosage or aggregate dosage of noribogaine or salt or solvate thereofis from about 1.3 mg/kg to about 5 mg/kg body weight. In a preferredembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. Inone embodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 2 mg/kg body weight. The ranges include bothextremes as well as any subranges there between.

In one embodiment, the dosage or aggregate dosage of noribogaine or saltor solvate thereof is about 8 mg/kg body weight per day. In oneembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 7 mg/kg body weight per day. In one embodiment,the dosage or aggregate dosage of noribogaine or salt or solvate thereofis about 6 mg/kg body weight per day. In one embodiment, the dosage oraggregate dosage of noribogaine or salt or solvate thereof is about 5mg/kg body weight per day. In one embodiment, the dosage or aggregatedosage of noribogaine or salt or solvate thereof is about 4 mg/kg bodyweight per day. In one embodiment, the dosage or aggregate dosage ofnoribogaine or salt or solvate thereof is about 3 mg/kg body weight perday. In one embodiment, the dosage or aggregate dosage of noribogaine orsalt or solvate thereof is about 2 mg/kg body weight per day. In oneembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 1.7 mg/kg body weight per day. In oneembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 1.5 mg/kg body weight per day. In oneembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 1.3 mg/kg body weight per day. In oneembodiment, the dosage or aggregate dosage of noribogaine or salt orsolvate thereof is about 1 mg/kg body weight per day.

In some embodiments, the therapeutic dose of noribogaine or salt orsolvate thereof is a tapered dosing over a period of time, during whichthe patient is detoxified, for example, without suffering significantacute withdrawal symptoms. Without being bound by theory, it is believedthat tapering will allow the full therapeutic effect of noribogaine withless prolongation of the QT interval. Tapering involves administrationof one or more subsequently lower doses of noribogaine over time. Forexample, in some embodiments, the first tapered dose is about 50% toabout 95% of the first or original dose. In some embodiments, the secondtapered dose is about 40% to about 90% of the first or original dose. Insome embodiments, the third tapered dose is about 30% to about 85% ofthe first or original dose. In some embodiments, the fourth tapered doseis about 20% to about 80% of the first or original dose. In someembodiments, the fifth tapered dose is about 10% to about 75% of thefirst or original dose.

In some embodiments, the first tapered dose is given after the firstdose of noribogaine. In some embodiments, the first tapered dose isgiven after the second, third, or a subsequent dose of noribogaine. Thefirst tapered dose may be administered at any time after the previousdose of noribogaine. The first tapered dose can be given once, forexample, followed by subsequent further tapered doses, or it can begiven multiple times with or without subsequent, further tapered doses(e.g., second, third, fourth, etc. tapered doses), which likewise can begiven once or over multiple administrations, for example. In someembodiments, the first tapered dose is administered one hour, 6 hours,12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after theprevious dose of noribogaine. Similarly, second, third, fourth, etc.tapered doses, if given, can be given one hour, 6 hours, 12 hours, 18hours, 24 hours, 36 hours, 48 hours, or more after the previous dose ofnoribogaine.

In some embodiments, one tapered dose is given to achieve the desiredlower therapeutic dose. In some embodiments, two tapered doses are givento achieve the desired lower therapeutic dose. In some embodiments,three tapered doses are given to achieve the desired lower therapeuticdose. In some embodiments, four or more tapered doses are given toachieve the desired lower therapeutic dose. Determination of the tapereddoses, number of tapered doses, and the like can be readily made aqualified clinician.

In one embodiment, the QT interval is not prolonged more than about 50ms. In one embodiment, the QT interval is not prolonged more than about40 ms. In one embodiment, the QT interval is not prolonged more thanabout 30 ms. In one embodiment, the QT interval is not prolonged morethan about 20 ms. In one embodiment, prolongation of the QT interval isequivalent to or less than the prolongation observed formethadone-treated patients.

In some embodiments, the patient is administered periodically, such asonce, twice, three time, four times or five time daily with noribogaineor a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the administration is once daily, or once every second day,once every third day, three times a week, twice a week, or once a week.The dosage and frequency of the administration depends on the route ofadministration, dosage, age and body weight of the patient, condition ofthe patient, without limitation. Determination of dosage and frequencysuitable for the present technology can be readily made a qualifiedclinician.

Noribogaine or a pharmaceutically acceptable solvate or salt thereof,suitable for administration in accordance with the methods provideherein, can be suitable for a variety of delivery modes including,without limitation, oral and transdermal delivery. Compositions suitablefor internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous,intra-arterial, intramuscular, intraperitoneal, intracutaneous andsubcutaneous routes may also be used. Possible dosage forms includetablets, capsules, pills, powders, aerosols, suppositories, parenterals,and oral liquids, including suspensions, solutions and emulsions.Sustained release dosage forms may also be used. All dosage forms may beprepared using methods that are standard in the art (see e.g.,Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, EastonPa. 1980).

In a preferred embodiment, noribogaine or a pharmaceutically acceptablesalt or solvate thereof is administered orally, which may convenientlybe provided in tablet, caplet, sublingual, liquid or capsule form. Incertain embodiments, the noribogaine is provided as noribogaine HCl,with dosages reported as the amount of free base noribogaine. In someembodiments, the noribogaine HCl is provided in hard gelatin capsulescontaining only noribogaine HCl with no excipients.

The patient may suffer from addiction to any opioid or opiate oropioid-like drug. In a preferred embodiment, the opioid or opioid-likedrug is selected from the group consisting of heroin, cocaine, opiate,methadone, morphine, codeine, oxycodone, hydrocodone, andmethamphetamine. In one embodiment, the opioid or opioid-like drug isheroin. In one embodiment, the opioid or opioid-like drug is methadone.In one embodiment, the opioid or opioid-like drug is morphine.

Maintenance Administration

In one aspect, this invention relates to treatment or attenuation ofpost-acute withdrawal from opioids or opioid-like drug in an addictedpatient with a maintenance amount of noribogaine or pharmaceuticallyacceptable salt or solvate thereof.

In some aspects, this invention relates to a method to prevent relapseof opioid or opioid-like drug abuse in an addicted patient treated toameliorate said abuse, said method comprising periodically administeringto said patient a maintenance dosage of noribogaine.

In some embodiments, the patient undergoes long-term (e.g., one year orlonger) treatment with maintenance doses of noribogaine or salt orsolvate thereof. In some embodiments, the patient is treated for acutewithdrawal with therapeutic doses of noribogaine as described above, andthen the amount of noribogaine is reduced to maintenance levels afteracute withdrawal symptoms would be expected to have subsided. Acutewithdrawal symptoms generally are the most pronounced in the first 48 to72 hours after cessation of the drug of addiction, although acutewithdrawal may last as long as a week or more.

In some embodiments, the patient is administered a high (therapeutic)dose of noribogaine or pharmaceutically acceptable salt or solvatethereof for a period of time to ameliorate the most significant withdrawsymptoms, and then is administered a lower (maintenance) dose to preventrelapse to opioid or opioid-like drug use. In some embodiments, thepatient is administered a therapeutic dose of noribogaine orpharmaceutically acceptable salt or solvate thereof for a period of timeto ameliorate the most significant withdraw symptoms, and then isadministered a decreasing (tapered) amount of noribogaine orpharmaceutically acceptable salt or solvate thereof over time until themaintenance dose is reached.

In some embodiments, the maintenance dose of noribogaine orpharmaceutically acceptable salt or solvate thereof is 70% of thetherapeutic dose. In some embodiments, the maintenance dose is 60% ofthe therapeutic dose. In some embodiments, the maintenance dose is 50%of the therapeutic dose. In some embodiments, the maintenance dose is40% of the therapeutic dose. In some embodiments, the maintenance doseis 30% of the therapeutic dose. In some embodiments, the maintenancedose is 20% of the therapeutic dose. In some embodiments, themaintenance dose is 10% of the therapeutic dose.

In some embodiments, the maintenance average serum level of noribogaineis 70% of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 60%of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 50%of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 40%of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 30%of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 20%of the therapeutic average serum level of noribogaine. In someembodiments, the maintenance average serum level of noribogaine is 10%of the therapeutic average serum level of noribogaine.

In one embodiment, the therapeutic dose is tapered over time until thedesired maintenance dose is reached. For example, in some embodiments,the first tapered dose is about 50% to about 95% of the therapeuticdose. In some embodiments, the second tapered dose is about 40% to about90% of the therapeutic dose. In some embodiments, the third tapered doseis about 30% to about 85% of the therapeutic dose. In some embodiments,the fourth tapered dose is about 20% to about 80% of the therapeuticdose. In some embodiments, the fifth tapered dose is about 10% to about75% of the therapeutic dose. In some embodiments, one tapered dose isgiven to achieve the maintenance dose. In some embodiments, two tapereddoses are given to achieve the maintenance dose. In some embodiments,three tapered doses are given to achieve the maintenance dose. In someembodiments, four or more tapered doses are given to achieve themaintenance dose. Determination of the tapered doses, number of tapereddoses, and the like can be readily made a qualified clinician.

In one embodiment, the QT interval is not prolonged more than 30 ms. Ina preferred embodiment, the QT interval is not prolonged more than 20ms.

In some embodiments, the patient is administered periodically, such asonce, twice, three time, four times or five time daily with noribogaineor a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the administration is once daily, or once every second day,once every third day, three times a week, twice a week, or once a week.The dosage and frequency of the administration depends on the route ofadministration, content of composition, age and body weight of thepatient, condition of the patient, without limitation. Determination ofdosage and frequency suitable for the present technology can be readilymade a qualified clinician.

Noribogaine or a pharmaceutically acceptable salt or solvate thereof,suitable for administration in accordance with the methods provideherein, can be suitable for a variety of delivery modes including,without limitation, oral and transdermal delivery. Compositions suitablefor internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous,intra-arterial, intramuscular, intraperitoneal, intracutaneous andsubcutaneous routes may also be used. Possible dosage forms includetablets, capsules, pills, powders, aerosols, suppositories, parenterals,and oral liquids, including suspensions, solutions and emulsions.Sustained release dosage forms may also be used. All dosage forms may beprepared using methods that are standard in the art (see e.g.,Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, EastonPa. 1980).

In a preferred embodiment, noribogaine or a pharmaceutically acceptablesalt or solvate thereof is administered orally, which may convenientlybe provided in tablet, caplet, sublingual, liquid or capsule form. Incertain embodiments, the noribogaine is provided as noribogaine HCl,with dosages reported as the amount of free base noribogaine. In someembodiments, the noribogaine HCl is provided in hard gelatin capsulescontaining only noribogaine HCl with no excipients.

The patient may suffer from addiction to any opioid or opiate, oropioid-like drug. In a preferred embodiment, the opioid or opioid-likedrug is selected from the group consisting of heroin, cocaine, opiate,methadone, morphine, codeine, hydrocodone, oxycodone, andmethamphetamine. In one embodiment, the opioid or opioid-like drug isheroin. In one embodiment, the opioid or opioid-like drug is methadone.In one embodiment, the opioid or opioid-like drug is morphine.

Patient Pre-Screening and Monitoring

Pre-screening of patients before treatment with noribogaine and/ormonitoring of patients during noribogaine treatment may be required toensure that QT interval is not prolonged beyond a certain value. Forexample, QT interval greater than 500 ms can be considered dangerous forindividual patients. Pre-screening and/or monitoring may be necessary athigh levels of noribogaine treatment.

In a preferred embodiment, a patient receiving a therapeutic dose ofnoribogaine is monitored in a clinical setting. Monitoring may benecessary to ensure the QT interval is not prolonged to an unacceptabledegree. A “clinical setting” refers to an inpatient setting (e.g.,inpatient clinic, hospital, rehabilitation facility) or an outpatientsetting with frequent, regular monitoring (e.g., outpatient clinic thatis visited daily to receive dose and monitoring). Monitoring includesmonitoring of QT interval. Methods for monitoring of QT interval arewell-known in the art, for example by ECG.

In one embodiment, a patient receiving a maintenance dose of noribogaineis not monitored in a clinical setting. In one embodiment, a patientreceiving a maintenance dose of noribogaine is monitored periodically,for example daily, weekly, monthly, or occasionally.

In one aspect, this invention relates to a method for treating opioid oropioid-like drug abuse and/or symptoms of withdrawal in an addictedpatient, comprising selecting an opioid- or opioid-like drug-addictedpatient who is prescreened to evaluate the patient's expected tolerancefor prolongation of QT interval, administering to the patient a dosageof noribogaine or pharmaceutically acceptable salt or solvate thereofthat provides an average serum concentration of about 50 ng/mL to about850 ng/mL (AUC/24 h), said concentration being sufficient to inhibit orameliorate said abuse or symptoms while maintaining a QT interval ofless than 500 ms during said treatment. In some embodiments, theconcentration is sufficient to attenuate said abuse or symptoms whilemaintaining a QT interval of less than about 470 ms during treatment.Preferably, the concentration is sufficient to attenuate said abuse orsymptoms while maintaining a QT interval of less than about 450 msduring treatment. In one embodiment, the concentration is sufficient toattenuate said abuse or symptoms while maintaining a QT interval of lessthan about 420 ms during treatment.

In one embodiment, prescreening of the patient comprises ascertainingthat noribogaine treatment will not result in a QT interval over about500 ms. In one embodiment, prescreening of the patient comprisesascertaining that noribogaine treatment will not result in a QT intervalover about 470 ms. In one embodiment, prescreening comprisesascertaining that noribogaine treatment will not result in a QT intervalover about 450 ms. In one embodiment, prescreening comprisesascertaining that noribogaine treatment will not result in a QT intervalover about 420 ms. In one embodiment, prescreening comprises determiningthe patient's pre-treatment QT interval.

As it relates to pre-screening or pre-selection of patients, patientsmay be selected based on any criteria as determined by the skilledclinician. Such criteria may include, by way of non-limiting example,pre-treatment QT interval, pre-existing cardiac conditions, risk ofcardiac conditions, age, sex, general health, and the like. Thefollowing are examples of selection criteria for disallowing noribogainetreatment or restricting dose of noribogaine administered to thepatient: high QT interval before treatment (e.g., such that there is arisk of the patient's QT interval exceeding 500 ms during treatment);congenital long QT syndrome; bradycardia; hypokalemia or hypomagnesemia;recent acute myocardial infarction; uncompensated heart failure; andtaking other drugs that increase QT interval. In some embodiments, themethods can include selecting and/or administering/providing noribogaineto a patient that lacks one more of such criteria.

In one embodiment, this invention relates to pre-screening a patient todetermine if the patient is at risk for prolongation of the QT intervalbeyond a safe level. In one embodiment, a patient at risk forprolongation of the QT interval beyond a safe level is not administerednoribogaine. In one embodiment, a patient at risk for prolongation ofthe QT interval beyond a safe level is administered noribogaine at alimited dosage.

In one embodiment, this invention relates to monitoring a patient who isadministered a therapeutic dose of noribogaine. In one embodiment, thedose of noribogaine is reduced if the patient has serious adverse sideeffects. In one embodiment, the noribogaine treatment is discontinued ifthe patient has serious adverse side effects. In one embodiment, theadverse side effect is a QT interval that is prolonged beyond a safelevel. The determination of a safe level of prolongation is within theskill of a qualified clinician.

Kit of Parts

One aspect of this invention is directed to a kit of parts for thetreatment of opioid or opioid-like drug abuse and/or symptoms ofwithdrawal in an addicted patient, wherein the kit comprises acomposition comprising noribogaine or salt or solvate thereof and ameans for administering the composition to a patient in need thereof.The means for administration to a patient can include, for example, anyone or combination of noribogaine, or a noribogaine derivative, or apharmaceutically acceptable salt or solvate thereof, a transdermalpatch, a syringe, a needle, an IV bag comprising the composition, a vialcomprising the composition, an inhaler comprising the composition, etc.In one embodiment, the kit of parts further comprises instructions fordosing and/or administration of the composition.

In some aspects, the invention is directed to a kit of parts foradministration of noribogaine, the kit comprising multiple deliveryvehicles, wherein each delivery vehicle contains a discrete amount ofnoribogaine and further wherein each delivery vehicle is identified bythe amount of noribogaine provided therein; and optionally furthercomprising a dosing treatment schedule in a readable medium. In someembodiments, the dosing treatment schedule includes the amount ofnoribogaine required to achieve each average serum level is provided. Insome embodiments, the kit of parts includes a dosing treatment schedulethat provides an attending clinician the ability to select a dosingregimen of noribogaine based on the sex of the patient, mass of thepatient, and the serum level that the clinician desires to achieve. Insome embodiments, the dosing treatment schedule further providesinformation corresponding to the volume of blood in a patient based uponweight (or mass) and sex of the patient. In an embodiment, the storagemedium can include an accompanying pamphlet or similar writteninformation that accompanies the unit dose form in the kit. In anembodiment, the storage medium can include electronic, optical, or otherdata storage, such as a non-volatile memory, for example, to store adigitally-encoded machine-readable representation of such information.

The term “delivery vehicle” as used herein refers to any formulationthat can be used for administration of noribogaine to a patient.Non-limiting, exemplary delivery vehicles include caplets, pills,capsules, tablets, powder, liquid, or any other form by which the drugcan be administered. Delivery vehicles may be intended foradministration by oral, inhaled, injected, or any other means.

The term “readable medium” as used herein refers to a representation ofdata that can be read, for example, by a human or by a machine.Non-limiting examples of human-readable formats include pamphlets,inserts, or other written forms. Non-limiting examples ofmachine-readable formats include any mechanism that provides (i.e.,stores and/or transmits) information in a form readable by a machine(e.g., a computer, tablet, and/or smartphone). For example, amachine-readable medium includes read-only memory (ROM); random accessmemory (RAM); magnetic disk storage media; optical storage media; andflash memory devices. In one embodiment, the machine-readable medium isa CD-ROM. In one embodiment, the machine-readable medium is a USB drive.In one embodiment, the machine-readable medium is a Quick Response Code(QR Code) or other matrix barcode.

In some aspects, the machine-readable medium comprises software thatcontains information regarding dosing schedules for the unit dose formof noribogaine and optionally other drug information. In someembodiments, the software may be interactive, such that the attendingclinician or other medical professional can enter patient information.In a non-limiting example, the medical professional may enter the weightand sex of the patient to be treated, and the software program providesa recommended dosing regimen based on the information entered. Theamount and timing of noribogaine recommended to be delivered will bewithin the dosages that result in the serum concentrations as providedherein.

In some embodiments, the kit of parts comprises multiple deliveryvehicles in a variety of dosing options. For example, the kit of partsmay comprise pills or tablets in multiple dosages, such as 240 mg, 120mg, 90 mg, 60 mg, 30 mg, 20 mg, and/or 10 mg of noribogaine per pill.Each pill is labeled such that the medical professional and/or patientcan easily distinguish different dosages. Labeling may be based onprinting or embossing on the pill, shape of the pill, color of pill, thelocation of the pill in a separate, labeled compartment within the kit,and/or any other distinguishing features of the pill. In someembodiments, all of the delivery vehicles within a kit are intended forone patient. In some embodiments, the delivery vehicles within a kit areintended for multiple patients.

One aspect of this invention is directed to a kit of parts for thetreatment of opioid, or opioid-like drug, abuse and/or symptoms ofwithdrawal in an addicted patient, wherein the kit comprises a unit doseform of noribogaine or salt or solvate thereof. The unit dose formprovides a patient with an average serum level of noribogaine of fromabout 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL.

In some embodiments, the unit dose form comprises one or multipledosages to be administered periodically, such as once, twice, threetime, four times or five time daily with noribogaine or its prodrug. Insome embodiments, the administration is once daily, or once every secondday, once every third day, three times a week, twice a week, or once aweek. The dosage and frequency of the administration depends on criteriaincluding the route of administration, content of composition, age andbody weight of the patient, condition of the patient, sex of thepatient, without limitation, as well as by the severity of theaddiction. Determination of the unit dose form providing a dosage andfrequency suitable for a given patient can readily be made by aqualified clinician.

These dose ranges may be achieved by transdermal, oral, or parenteraladministration of noribogaine or a pharmaceutically acceptable salt orsolvate thereof in unit dose form. Such unit dose form may convenientlybe provided in transdermal patch, tablet, caplet, liquid or capsuleform. In certain embodiments, the noribogaine is provided as noribogaineHCl, with dosages reported as the amount of free base noribogaine. Insome embodiments, the noribogaine HCl is provided in hard gelatincapsules containing only noribogaine HCl with no excipients. In someembodiments, noribogaine is provided in saline for intravenousadministration.

Formulations

This invention further relates to pharmaceutically acceptableformulations comprising a unit dose of noribogaine or pharmaceuticallyacceptable salt or solvate thereof, wherein the amount of noribogaine issufficient to provide an average serum concentration of about 50 ng/mLto about 850 ng/mL (AUC/24 h) when administered to a patient. In apreferred embodiment, the amount of noribogaine is sufficient to providean average serum concentration of about 50 ng/mL to about 400 ng/mL(AUC/24 h) when administered to a patient.

In some embodiments, the unit dose of noribogaine is administered in oneor more dosings.

In one embodiment, the amount of noribogaine is sufficient to provide anaverage serum concentration of noribogaine from about 50 ng/mL to about800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, theamount of noribogaine is sufficient to provide an average serumconcentration of noribogaine from about 50 ng/mL to about 700 ng/mL orabout 60 ng/mL to about 700 ng/mL. In one embodiment, the amount ofnoribogaine is sufficient to provide an average serum concentration ofnoribogaine from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL toabout 600 ng/mL. In a preferred embodiment, the amount of noribogaine issufficient to provide an average serum concentration of noribogaine fromabout 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL.In one embodiment, the amount of noribogaine is sufficient to provide anaverage serum concentration of noribogaine from about 50 ng/mL to about400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, theamount of noribogaine is sufficient to provide an average serumconcentration of noribogaine from about 50 ng/mL to about 300 ng/mL, orabout 60 ng/mL to about 300 ng/mL. In one embodiment, the amount ofnoribogaine is sufficient to provide an average serum concentration ofnoribogaine from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL toabout 200 ng/mL. In one embodiment, the amount of noribogaine issufficient to provide an average serum concentration of noribogaine fromabout 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL.The ranges include both extremes as well as any subranges between.

In some embodiments, the formulation is designed for periodicadministration, such as once, twice, three time, four times or five timedaily with noribogaine or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the administration is once daily, or onceevery second day, once every third day, three times a week, twice aweek, or once a week. The dosage and frequency of the administrationdepends on the route of administration, content of composition, age andbody weight of the patient, condition of the patient, withoutlimitation. Determination of dosage and frequency suitable for thepresent technology can be readily made a qualified clinician.

In some embodiments, the formulation designed for administration inaccordance with the methods provide herein can be suitable for a varietyof delivery modes including, without limitation, oral and transdermaldelivery. Formulations suitable for internal, pulmonary, rectal, nasal,vaginal, lingual, intravenous, intra-arterial, intramuscular,intraperitoneal, intracutaneous and subcutaneous routes may also beused. Possible formulations include tablets, capsules, pills, powders,aerosols, suppositories, parenterals, and oral liquids, includingsuspensions, solutions and emulsions. Sustained release dosage forms mayalso be used. All formulations may be prepared using methods that arestandard in the art (see e.g., Remington's Pharmaceutical Sciences, 16thed., A. Oslo editor, Easton Pa. 1980).

In a preferred embodiment, the formulation is designed for oraladministration, which may conveniently be provided in tablet, caplet,sublingual, liquid or capsule form. In certain embodiments, thenoribogaine is provided as noribogaine HCl, with dosages reported as theamount of free base noribogaine. In some embodiments, the noribogaineHCl is provided in hard gelatin capsules containing only noribogaine HClwith no excipients.

EXAMPLES

The following Examples are intended to further illustrate certainembodiments of the disclosure and are not intended to limit its scope.

Example 1 Pharmacokinetics and Pharmacodynamics of Noribogaine in Humans

Thirty-six healthy, drug-free male volunteers, aged between 18-55 years,were enrolled in and completed the study. This was an ascendingsingle-dose, placebo-controlled, randomized double blind, parallel groupstudy. Mean (SD) age was 22.0 (3.3) years, mean (SD) height was 1.82(0.08) m, and mean (SD) weight was 78.0 (9.2) kg. Twenty-six subjectswere Caucasian, 3 were Asian, 1 Maori, 1 Pacific Islander, and 5 Other.The protocol for this study was approved by the Lower South RegionalEthics Committee (LRS/12/06/015), and the study was registered with theAustralian New Zealand Clinical Trial Registry (ACTRN12612000821897).All subjects provided signed informed consent prior to enrolment, andwere assessed as suitable to participate based on review of medicalhistory, physical examination, safety laboratory tests, vital signs andECG.

Within each dose level, 6 participants were randomized to receivenoribogaine and 3 to receive placebo, based on a computer-generatedrandom code. Dosing began with the lowest noribogaine dose, andsubsequent cohorts received the next highest dose after the safety,tolerability, and blinded pharmacokinetics of the completed cohort werereviewed and dose-escalation approved by an independent Data SafetyMonitoring Board. Blinded study drug was administered as a capsule with240 ml of water after an overnight fast of at least 10 hours.Participants did not receive any food until at least 5 hours post-dose.Participants were confined to the study site from 12 hours prior to drugadministration, until 72 hours post-dose, and there were subsequentoutpatient assessments until 216 hours post-dose.

Blood was obtained for pharmacokinetic assessments pre-dose and then at0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7,8, 10, 12, 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hourspost-dose. Samples were centrifuged and plasma stored at −70° C. untilanalyzed. Block 24 hour urine collections were obtained following studydrug administration for the 30 and 60 mg cohorts. Aliquots were frozenat −20° C. until analyzed.

Pulse oximetry and capnography data were collected continuously using aGE Carescape B650 monitoring system from 2 hours prior to dosing anduntil six hours after dosing, and thereafter at 12, 24, 48 and 72 hourspost-dosing. Additional oximetry data were collected at 120, 168 and 216hours. Pupillary miosis was assessed by pupillometry. Dark-adapted pupildiameter was measured in triplicate using a Neuroptics PLR-200pupillometer under standardized light intensity (<5 lux) pre-dose, andat 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 hours post-dosing.

Plasma noribogaine concentrations were determined in the 3 mg and 10 mgdose groups using a validated, sensitive LCMSMS method. Samplepreparation involved double extraction of basified plasma samples withtert-butyl methyl ether, drying the samples under a stream of nitrogenand reconstitution of sample with acetonitrile:B.P. water (5:95, v/v)containing 0.1% (v/v) formic acid. The compounds were separated by a150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupoleAPI 4000 or 5000 mass spectrometer using electrospray ionization inpositive mode and multiple reaction monitoring. Noribogaine-d₄ was usedas the internal standard. The precursor-product ion transition valuesfor noribogaine were m/z 297.6→122.3, and for the internal standardnoribogaine-d₄ m/z 301.1→122.2. Analyst® software was used for dataacquisition and processing. The ratio of the peak area of noribogaine tothe internal standard noribogaine-d₄ was used for calibration andmeasurement of the unknown concentration of noribogaine. The lower limitof quantification (LLOQ) was 0.025 ng/ml noribogaine. The calibrationcurve was between 0.025 and 25.600 ng/ml noribogaine. Mobile phase A wasacetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid,and mobile phase B was acetonitrile:B.P. water (95:5, v/v) containing0.1% (v/v) formic acid. Total run time was 6 minutes. Binary flow:Initial concentration was 8% mobile phase B; hold at 8% mobile phase Bfor 0.5 minutes and linear rise to 90% mobile phase B over 1.5 minutes;hold at 90% mobile phase B for 1 minute and then drop back to 8% mobilephase B over 0.01 minute. Equilibrate system for 3 minutes. Total runtime was 6 minutes. Within- and between-day assay precision was <9%, andwithin- and between-day assay accuracy was <9%.

Plasma noribogaine concentrations were determined in the 30 mg and 60 mgdose groups using a validated, sensitive LCMSMS method. Samplepreparation involved deproteinization of plasma samples withacetonitrile and dilution of sample with 0.1% (v/v) formic acid. Thecompounds were separated by a 150×2.0 mm Luna 5 μm C18 column anddetected with a triple—quadrupole API 4000 or 5000 mass spectrometerusing electrospray ionization in positive mode and multiple reactionmonitoring. Noribogaine-d₄ was used as the internal standard. Theprecursor-product ion transition values for noribogaine were m/z297.6→122.3, and for the internal standard noribogaine-d₄ m/z301.1→122.2. Analyst® software was used for data acquisition andprocessing. The ratio of the peak area of noribogaine to the internalstandard noribogaine-d₄ was used for calibration and measurement of theunknown concentration of noribogaine. The LLOQ was 0.50 ng/mlnoribogaine. The calibration curve was between 0.50 and 256.00 ng/mlnoribogaine. Mobile phase was the same as method A, and binary flow wasalso the same as method A. The within- and between-day assay precisionwas <9%, and the within- and between-day assay accuracy was <9%.

Plasma noribogaine glucuronide concentrations were determined in the 30mg and 60 mg dose groups using a validated sensitive LCMSMS method.Sample preparation involved deproteinization of plasma samples withacetonitrile, drying the samples under a stream of nitrogen andreconstitution of sample with acetonitrile:B.P. water (5:95, v/v)containing 0.1% (v/v) formic acid. The compounds were separated by a150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupoleAPI 4000 or 5000 mass spectrometer using electrospray ionization inpositive mode and multiple reaction monitoring. Noribogaine-d₄ was usedas the internal standard. The precursor-product ion transition valuesfor noribogaine glucuronide were m/z 472.8→297.3, and for the internalstandard noribogaine-d₄ m/z 301.1→122.2. Analyst® software was used fordata acquisition and processing. The ratio of the peak area ofnoribogaine glucuronide to the internal standard noribogaine-d₄ was usedfor calibration and measurement of the unknown concentration ofnoribogaine glucuronide. The LLOQ was 0.050 ng/ml noribogaineglucuronide. The calibration curve was between 0.050 and 6.400 ng/mlnoribogaine glucuronide. Mobile phases was the same as method A. Binaryflow: Initial concentration was 6% mobile phase B; hold at 6% mobilephase B for 0.5 minutes and linear rise to 90% mobile phase B over 2minutes; hold at 90% mobile phase B for 1 minute and then drop back to6% mobile phase B over 0.01 minute. Equilibrate system for 3.5 minutes.Total run time was 7 minutes. The within- and between-day assayprecision was <11%, and the within- and between-day assay accuracy was<10%.

Urine noribogaine and noribogaine glucuronide concentrations weredetermined in the 30 mg and 60 mg dose groups using a validatedsensitive LCMSMS method. Sample preparation involved deproteinization ofurine samples with acetonitrile and dilution of the sample with 0.1%(v/v) formic acid. The compounds were separated by a 150×2.0 mm Luna 5μm C18 column and detected with a triple—quadrupole API 5000 massspectrometer using electrospray ionization in positive mode and multiplereaction monitoring. Noribogaine-d₄ was used as the internal standard.The precursor-product ion transition values for noribogaine were m/z297.6→122.3, noribogaine glucuronide m/z 472.8→297.3, and for theinternal standard noribogaine-d₄ m/z 301.1→122.2. Analyst® software wasused for data acquisition and processing. The ratios of the peak area ofnoribogaine and noribogaine glucuronide to the internal standardnoribogaine-d₄ were used for calibration and measurement of the unknownconcentration of noribogaine and its glucuronide. Assay LLOQ was 20.0ng/ml for noribogaine and 2.0 ng/ml for noribogaine glucuronide. Thecalibration curve was between 20.0 and 5120.0 ng/ml noribogaine, and 2.0and 512.0 ng/ml noribogaine glucuronide. Mobile phases were as describedin method A, and binary flow as in method C. The within- and between-dayassay precision was <13%, and within- and between-day assay accuracy was<12%.

Noribogaine and noribogaine glucuronide concentrations above the limitof quantification were used to calculate pharmacokinetic parametersusing model-independent methods. The maximum plasma concentration (Cmax)and time to maximum plasma concentration (Tmax) were the observedvalues. Plasma concentration data in the post-distribution phase of theplasma concentration-time plot were fitted using linear regression tothe formula ln C=ln Co−t.Kel, where Co was the zero-time intercept ofthe extrapolated terminal phase and Kel was the terminal eliminationrate constant. The half-life (t_(1/2)) was determined using the formulat_(1/2)=0.693/Kel. The area under the concentration-time curve (AUC)from time zero to the last determined concentration-time point (tf) inthe post distribution phase was calculated using the trapezoidal rule.The area under the curve from the last concentration-time point in thepost distribution phase (Ctf) to time infinity was calculated fromAUC_(t-∞)=Ctf/Kel. The concentration used for Ctf was the lastdetermined value above the LLOQ at the time point. The total AUC_(0-∞)was obtained by adding AUC_(tf) and AUC_(t-∞). Noribogaine apparentclearance (CL/F) was determined using the formulaCL/F=Dose/AUC_(0-∞)×1000, and apparent volume of distribution (Vd/F) wasdetermined using the formula Vd/F=(CL/F)/Kel. Total urine noribogainewas the sum of both analytes.

Summary statistics (means, standard deviations, and coefficients ofvariation) were determined for each dose group for safety laboratorytest data, ECG and pharmacokinetic parameters, and pharmacodynamicvariables. Categorical variables were analysed using counts andpercentages. Dose-proportionality of AUC and Cmax was assessed usinglinear regression. The effect of dose on pharmacodynamic parametervalues over time was assessed using two-factor analysis of variance(ANOVA). Pairwise comparisons (with Tukey-Kramer adjustment) betweeneach dose group to the placebo were conducted at each time point usingthe least squares estimates obtained from the ANOVA, using SAS ProcMixed (SAS ver 6.0).

Results

Pharmacokinetics: Mean plasma concentration-time plots of noribogaineare shown in FIG. 1, and mean pharmacokinetic parameters are shown inTable 1.

TABLE 1 3 mg (n = 6) 10 mg (n = 6) 30 mg (n = 6) 60 mg (n = 6)Noribogaine (mean (SD)) (mean (SD)) (mean (SD)) (mean (SD) AUC_(0-∞)74.2 (13.1) 254.5 (78.9)  700.4 (223.3) 1962.2 (726.5)  (ng · hr/ml)AUC₀₋₂₁₆ 72.2 (13.2) 251.4 (78.5)  677.6 (221.1) 1935.4 (725.4)  (ng ·hr/ml) Cmax 5.2 (1.4) 14.5 (2.1)  55.9 (14.8) 116.0 (22.5)  (ng/ml) Tmax(hr) 1.9 (0.6) 2.9 (1.8) 1.8 (0.6) 2.4 (0.6) t_(1/2) (hr) 40.9 (8.7) 49.2 (11.5) 27.6 (7.0))  29.1 (9.3)  Vd/F (L) 2485.1 (801.5)  3085.8(1197.0) 1850.8 (707.9)  1416.8 (670.1)  CL/F (L/h) 41.4 (7.0)  42.3(12.0) 46.9 (16.4) 34.0 (11.4) Noribogaine glucuronide AUC_(0-∞) — —25.8 (9.3) 67.1 (21.9) (ng · hr/ml) AUC₀₋₂₁₆ — — 25.7 (9.1) 65.0 (21.5)(ng · hr/ml) Cmax — — 1.8 (0.6) 4.1 (1.2) (ng/ml) Tmax (hr) — — 3.0(0.6) 3.8 (1.2) t_(1/2) (hr) — — 20.6 (4.9)  23.1 (3.0) 

Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3hours after oral dosing. Fluctuations in individual distribution-phaseconcentration-time profiles may suggest the possibility of enterohepaticrecirculation (see highlighted individual 4-8 hour profiles in FIG. 1,insert). Both Cmax and AUC increased linearly with dose (Table 1, upperpanel). Mean half-life estimates of 28-50 hours were observed acrossdose groups for noribogaine. Volume of distribution was extensive(1417-3086 L across dose groups).

Mean plasma noribogaine glucuronide concentration-time plots for the 30mg and 60 mg dose group are shown in FIG. 2, and mean pharmacokineticparameters are shown in Table 1, lower panel. Noribogaine glucuronidewas detected in all subjects by 0.75 hours, with peak concentrationsoccurring 3-4 hours after noribogaine dosing. Mean half-life of 21-23hours was estimated for plasma noribogaine glucuronide. The proportionof noribogaine glucuronide Cmax and AUC relative to noribogaine was 3-4%for both dose groups. Total urine noribogaine elimination was 1.16 mgand 0.82 mg for the 30 mg and 60 mg dose groups respectively,representing 3.9% and 1.4% of the doses administered.

Pharmacodynamics: There was no evidence of pupillary constriction insubjects dosed with noribogaine. No between-dose group differences inpupil diameter were detected over time. After adjusting for baselinedifferences, comparison of each dose group with placebo by ANOVA showedno statistically significant differences (p>0.9).

Noribogaine treatment showed no analgesic effect in the cold pressortest. Analgesic effect was assessed based on duration of hand immersionin ice water and on visual analog scale (VAS) pain scores upon handremoval from the water bath. For duration of hand immersion, afteradjusting for baseline differences, comparison of each dose group withplacebo by ANOVA showed no statistically significant differences(p>0.9). Similarly, for VAS pain scores, after adjusting for baselinedifferences, comparison of each dose group with placebo by ANOVA showedno statistically significant differences (p=0.17).

Example 2 Safety and Tolerability of Noribogaine in Humans

Safety and tolerability of noribogaine were tested in the group ofvolunteers from Example 1. Cold pressor testing was conducted in 1° C.water according to the method of Mitchell et al. (J Pain 5:233-237,2004) pre-dose, 6, 24, 48, 72 and 216 hours post-dosing. Safetyevaluations included clinical monitoring, recording of adverse events(AEs), safety laboratory tests, vital signs, ECG telemetry from −2 h to6 h after dosing, and 12-lead electrocardiograms (ECGs) up to 216 hourspost-dosing.

Results

A total of thirteen adverse events were reported by seven participants(Table 2). Six adverse events were reported by three participants in theplacebo group, five adverse events were reported by two subjects in the3 mg dose group, and one adverse event was reported by single subjectsin the 10 mg and 30 mg dose groups, respectively. The most commonadverse events were headache (four reports) and epistaxis (two reports).All adverse events were of mild-moderate intensity, and all resolvedprior to study completion. There were no changes in vital signs orsafety laboratory tests of note. In particular, there were no changes inoximetry or capnography, or changes in respiratory rate. There were noQTcF values >500 msec at any time. One subject dosed with 10 mgnoribogaine had a single increase in QTcF of >60 msec at 24 hourspost-dosing.

TABLE 2 Dose (mg) Mild Moderate Severe Placebo Blepharitis Epistaxis —Bruising Dry Skin Eye pain, nonspecific Infection at cannula site  3Back pain Headache — Dizziness Epistaxis Headache 10 Headache — — 30Headache — — 60 — — —

Example 3 Efficacy of Noribogaine in Humans

The efficacy of noribogaine in humans was evaluated in opioid-dependentparticipants in a randomized, placebo-controlled, double-blind trial.Patients had been receiving methadone treatment as the opioidsubstitution therapy, but were transferred to morphine treatment priorto noribogaine administration. This was done to avoid negativenoribogaine-methadone interactions that are not observed betweennoribogaine and methadone. See U.S. Provisional Application Ser. No.61/852,485, filed Mar. 15, 2013, which is incorporated herein byreference in its entirety.

In the first cohort, six patients were orally administered a single doseof 60 mg noribogaine, and three patients received placebo. In the secondcohort, five patients were orally administered a single dose of 120 mgnoribogaine, and three patients received placebo. Treatment wasadministered 2 hours after last morphine dose and the time to resumptionof morphine (opioid substitution treatment, OST) was determined. Noadverse effects of noribogaine were observed in any of the participants,including no hallucinatory effects.

FIG. 3 indicates the serum noribogaine concentration over time. Serumconcentrations for 120 mg dose (black squares) are estimated based ondata from the 60 mg dose (gray diamonds).

Blinded Results

Patients in the first cohort exhibited an average time to resumption ofopioids after treatment with 60 mg noribogaine or placebo ofapproximately 8.7 hours, which is almost 2 hours longer than thatreported for untreated patients in a similar study. Patients in thesecond cohort exhibited an average time to resumption of opioids aftertreatment with 120 mg noribogaine or placebo of approximately 23 hours.FIG. 4A indicates the average time to resumption of morphine for control(untreated, light gray bar), first cohort (dark gray bar) and secondcohort (black bar). Mean prolongation of the QT interval was less than10 ms for patients in the first cohort and was less than 40 ms in thesecond cohort.

FIG. 4B indicates the estimated noribogaine concentration (based on thedata from FIG. 3) at the time of resumption of morphine for eachpatient.

Although the study was blinded, the three patients in the second cohortwho received placebo were construed to be those patients exhibiting noprolongation of the QT interval. The average time to resumption of OSTfor the remaining five patients was determined to be approximately 26.8hours, as indicated in FIG. 5A (black bar). FIG. 5B indicates theestimated noribogaine concentration (based on the data from FIG. 3) atthe time of resumption of morphine for each (presumed)noribogaine-treated patient. FIG. 5B demonstrates that, as serumconcentrations of noribogaine reach an estimated level of 50 to 60ng/mL, significant withdrawal symptoms return such that the patient isforced to resume OST. At serum noribogaine levels above about 50 to 60ng/mL, the patients did not exhibit withdrawal symptoms or thosesymptoms had not become acute.

What is claimed is:
 1. A method for treating opioid or opioid-like drugabuse in a human patient addicted thereto, comprising administering tothe patient an aggregate dosage of noribogaine or pharmaceuticallyacceptable salt or solvate thereof that provides an average serumconcentration of about 50 ng/mL to about 500 ng/mL, said concentrationbeing sufficient to inhibit or ameliorate said abuse while targeting amaximum QT interval prolongation of less than about 40 millisecondsduring said treatment, wherein the aggregate dosage of noribogaine orpharmaceutically acceptable salt or solvate thereof is from about 60 mgto about 120 mg per day.
 2. The method of claim 1, wherein the aggregatedosage of noribogaine or pharmaceutically acceptable salt or solvatethereof is administered as a single dose or multiple doses.
 3. Themethod of claim 1, wherein the aggregate dosage of noribogaine orpharmaceutically acceptable salt or solvate thereof is about 120 mg perday.
 4. The method of claim 1, wherein the aggregate dosage ofnoribogaine or pharmaceutically acceptable salt or solvate thereofprovides an average serum concentration of about 50 ng/mL to about 200ng/mL.
 5. The method of claim 1, wherein the QT interval prolongationprovides for a QT interval to be maintained at less than about 470milliseconds during said treatment.
 6. The method of claim 5, whereinthe patient's QT interval is maintained at less than about 450milliseconds during said treatment.
 7. The method of claim 1, furthercomprising selecting an addicted patient who is prescreened to evaluatetolerance for prolongation of QT interval.
 8. The method of claim 7,wherein the prescreening step comprises ascertaining that noribogainetreatment will not result in a QT interval greater than about 500milliseconds.
 9. The method of claim 8, wherein the prescreening stepcomprises ascertaining that noribogaine treatment will not result in aQT interval greater than about 470 milliseconds.
 10. The method of claim8, wherein the prescreening step comprises ascertaining that noribogainetreatment will not result in a QT interval greater than about 450milliseconds.
 11. A method for attenuating withdrawal symptoms in ahuman patient susceptible to such symptoms due to opioid or opioid-likedrug addiction, comprising administering to the patient an aggregatedosage of noribogaine or pharmaceutically acceptable salt or solvatethereof that provides an average serum concentration of about 50 ng/mLto about 400 ng/mL, said concentration being sufficient to attenuatesaid symptoms while targeting a maximum QT interval prolongation of lessthan about 40 milliseconds during said treatment, wherein the aggregatedosage of noribogaine or pharmaceutically acceptable salt or solvatethereof is from about 60 mg to about 120 mg per day.
 12. The method ofclaim 11, wherein the withdrawal symptoms are due to acute withdrawal.13. The method of claim 11, wherein the aggregate dosage of noribogaineor pharmaceutically acceptable salt or solvate thereof is administeredas a single dose or multiple doses.
 14. The method of claim 11, whereinthe aggregate dosage of noribogaine or pharmaceutically acceptable saltor solvate thereof is about 120 mg per day.
 15. The method of claim 11,wherein the QT interval prolongation provides for a QT interval to bemaintained at less than about 470 milliseconds during said treatment.16. The method of claim 15, wherein the patient's QT interval ismaintained at less than about 450 milliseconds during said treatment.